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Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis (INFU/PARA)

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ClinicalTrials.gov Identifier: NCT01540838
Recruitment Status : Completed
First Posted : February 29, 2012
Results First Posted : September 24, 2019
Last Update Posted : September 24, 2019
Sponsor:
Collaborator:
Foundation for Paediatric Research, Finland
Information provided by (Responsible Party):
Heikki Peltola, MD, PhD, Helsinki University

Tracking Information
First Submitted Date  ICMJE February 23, 2012
First Posted Date  ICMJE February 29, 2012
Results First Submitted Date  ICMJE February 21, 2019
Results First Posted Date  ICMJE September 24, 2019
Last Update Posted Date September 24, 2019
Actual Study Start Date  ICMJE February 2012
Actual Primary Completion Date February 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 22, 2019)
Day 7 Mortality [ Time Frame: On day 7 from the institution of treatment ]
All patients who had received at least one dose of treatment and were dead on day 7 from the institution of treatment on day 1.
Original Primary Outcome Measures  ICMJE
 (submitted: February 28, 2012)
Mortality [ Time Frame: On day 7 from the institution of treatment ]
All patients should stay in hospital ≥7 days.
Change History Complete list of historical versions of study NCT01540838 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2019)
  • All Deaths During Hospital Stay [ Time Frame: The outcome was assessed each day until the patient was discharged from the hospital. The longest hospital stay was 84 days, while the last death occurred 39 days after treatment initiation. ]
    All patients who had received at least one dose of treatment and died during the hospital stay.
  • Status on the Modified Glasgow Outcome Scale [ Time Frame: Examined at discharge from hospital, except for hearing evaluations which were performed at earliest seven days since the institution of treatment, during the hospital stay. The longest hospital stay was 84 days. ]
    Scores on the modified Glasgow Outcome Scale which range from a maximum of 5 (best) to a minimum of 1 (worst) points. The Glasgow Outcome Scale categorizes the outcome after brain injury into five categories, based on the level and severeness of disability. As hearing impairment is one of the most common sequelae of bacterial meningitis, an assessment of hearing should be included when estimating the grade of disability. Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately.
  • Death or Any Neurological Sequelae on Day 7 [ Time Frame: Examined on day 7 since institution of treatment. ]
    Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
  • A Change in Hearing Threshold Compared to the First Test Result [ Time Frame: Hearing thresholds obtained during any of the first three days after hospital admission were compared with hearing thresholds obtained on day seven or later, during the hospital stay. The longest hospital stay was 84 days. ]
    Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. The better ear's hearing threshold, obtained on admission or shortly thereafter, was compared with the better ear's hearing threshold obtained at earliest after one week of treatment.
  • Death or Severe Neurological Sequelae on Day 7 [ Time Frame: Examined on day 7 since institution of treatment ]
    Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
  • Number of Participants With Deafness [ Time Frame: This outcome includes hearing thresholds determined at earliest seven days after the institution of treatment, during the hospital stay. The longest hospital stay was 84 days. ]
    Hearing thresholds (in decibel, dB) were determined by brainstem evoked response audiometry (BERA), for each ear separately. Deafness was defined as a hearing threshold >80 dB in the better ear.
  • Death or Any Neurological Sequelae at Discharge From Hospital. [ Time Frame: Examined at discharge from hospital. The longest hospital stay was 84 days. ]
    Defined as death or any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree.
  • Death or Severe Neurological Sequelae at Discharge [ Time Frame: Examined at discharge from hospital. The longest hospital stay was 84 days. ]
    Death or severe neurological sequelae, defined as blindness, tetraplegia/paresis, hydrocephalus requiring a shunt and severe psychomotor retardation
Original Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2012)
  • Mortality [ Time Frame: On days 14, 21, and 28 from the institution of treatment. ]
  • Status on the Modified Glasgow Outcome Scale [ Time Frame: Examined on days 7, 14, 21, and 28 since institution of treatment ]
    Scores from 5 to 1
  • Death or any sequelae [ Time Frame: Examined on days 7, 14, 21, and 28 since institution of treatment ]
    Defined as any severe neurological sequelae, or hemi- or monoparesis, or ataxia, or psychomotor retardation of any degree, or any hearing impairment. Hearing is deemed impaired if the better ear fails to detect a threshold of 40 dB. The cut-off levels for moderate and severe hearing impairment are 60 dB and 80 dB, respectively.
  • A change in hearing threshold compared to the first test result [ Time Frame: Examined on days 7, 14, 21, and 28 since instituion of treatment ]
    Hearing thresholds are determined by an independent observer on the bases of the BERA register, for each ear separately.
  • Death or severe neurological sequelae [ Time Frame: Examined on days 7, 14, 21 and 28 since institution of treatment ]
    Severe neurological sequelae are defined as blindness, tetraplegia/paresia, hydrocephalus requiering a shunt and severe prychomotor retardation
  • Deafness [ Time Frame: Examined on days 7, 14, 21 and 28 since initiation of treatment ]
    Defined as a hearing threshold >80dBs in the better ear.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis
Official Title  ICMJE Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis, Especially of Pneumococcal Meningitis, in Angola.
Brief Summary

The main purpose of this trial is to test if mortality of childhood bacterial meningitis can be reduced by slow, continuous infusion of cefotaxime initially, instead of the traditional bolus administration four times daily (qid), combined with high-dose paracetamol orally, when both treatments are executed for the first 4 days. The series will be collected at Hospital Pediátrico David Bernardino, Luanda, Angola.

The recruitment of patients begins, the conditions permitting, in early 2012. The criteria for patient participation is a child at the age of 2 months to 15 years who presents with the symptoms and signs suggestive of bacterial meningitis, for whom a lumbar puncture is performed, and the cerebrospinal fluid analysis suggests bacterial meningitis.

Detailed Description

The principal objective of the study is to examine if mortality of childhood bacterial meningitis can be reduced by slow continuous infusion of cefotaxime combined with high-dose paracetamol orally for the first 4 days (instead of the traditional qid administration of cefotaxime without concomitant paracetamol). Children qualifying for entry (see criteria below), whose guardian has given informed consent,will be randomized into 2 treatment arms (see details below)and receive the treatments in a double blind fashion (see details below). Primary and secondary outcomes (detailed below) will be evaluated according to predefined criteria and time points (see below).

Results will be analyzed for all patients in ITT datasets and in prespecified subgroups (etiology, nutritional status, etc.) in both crude and adjusted analysis. The efficacy results will be expressed as OR with 95% confidence intervals.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Bacterial Meningitis
Intervention  ICMJE
  • Drug: Infusion with paracetamol
    The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.
    Other Name: paracetamol=acetaminophen
  • Drug: Bolus without paracetamol
    The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.
    Other Name: Paracetamol=acetaminophen
Study Arms  ICMJE
  • Experimental: Infusion with paracetamol
    Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen)
    Intervention: Drug: Infusion with paracetamol
  • Active Comparator: Bolus with placebo
    Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol
    Intervention: Drug: Bolus without paracetamol
Publications * Pelkonen T, Roine I, Cruzeiro ML, Pitkäranta A, Kataja M, Peltola H. Slow initial β-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial. Lancet Infect Dis. 2011 Aug;11(8):613-21. doi: 10.1016/S1473-3099(11)70055-X. Epub 2011 May 5.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 26, 2017)
375
Original Estimated Enrollment  ICMJE
 (submitted: February 28, 2012)
400
Actual Study Completion Date  ICMJE February 2017
Actual Primary Completion Date February 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Eligibility criteria:

The study entry is assessed for all children at age 2 months - 15 years who present at these centers with the symptoms and signs suggestive of bacterial meningitis (BM), and to whom lumbar puncture is performed.

Inclusion criteria:

All patients whose cerebrospinal fluid (CSF) turns out to be cloudy, positive by Gram staining or latex agglutination, or shows at least 50 leukocytes per mm3, will be enrolled in the study.

Participants: Exclusion criteria

Exclusion criteria:

  1. Trauma, or relevant underlying illness such as intracranial shunt, previous neurological abnormality (cerebral palsy, Down's syndrome, meningitis)
  2. Previous hearing impairment (if known)
  3. Immunosuppression, except HIV infection
  4. More than one parenteral dose of a pretreatment antimicrobial. Children with oral antimicrobials are included, this information being marked in the FOLLOW-UP sheet.
  5. Active tuberculosis (if tuberculotic meningitis is diagnosed during trial, it will be included in intention-to-treat (ITT) analysis)
  6. Known hepatic disease.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Months to 15 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Angola
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01540838
Other Study ID Numbers  ICMJE INFU/PARA-BOLU/PLACE
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: We are working on an agreement to share data with all the participants,
Responsible Party Heikki Peltola, MD, PhD, Helsinki University
Study Sponsor  ICMJE Helsinki University
Collaborators  ICMJE Foundation for Paediatric Research, Finland
Investigators  ICMJE
Study Director: Heikki O Peltola, MD, PhD Childrens Hospital of Helsinki University Central Hospital
PRS Account Helsinki University
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP